Piperidinetriol derivatives as inhibitors of glycosylceramidsynthase

ABSTRACT

Compounds of formula (I); wherein R represents various substituent groups, are useful as inhibitors of glucosylceramide synthase.

The present invention relates to novel piperidine derivatives useful asinhibitors of glucosylceramide synthase (GCS; UDP-glucose:ceramideglucosyltransferase, UDP-glucose:N-acylsphingosineD-glucosyltransferase, EC 2.4.1.80), methods for their preparation andtheir use in medicine, specifically in the treatment and prevention ofdisease states mediated by GCS. The compounds find use in the treatmentof glycolipid storage diseases, diseases associated with glycolipidaccumulation, cancers in which glycolipid synthesis is abnormal,infectious diseases caused by organisms which use cell surfaceglycolipids as receptors, infectious diseases in which synthesis ofglucosylceramide is essential or important, diseases in which excessiveglycolipid synthesis occurs, neuronal disorders, neuronal injury andinflammatory diseases or disorders associated with macrophagerecruitment and activation.

GCS is an intracellular enzyme that catalyzes the assembly of uridinediphosphate-glucose and ceramide into the glycolipid, glucosylceramide.The role of GCS in regulating ceramide levels has been explored, sincethis molecule can induce apoptotic cell death (J. Biol. Chem., 2000,275(10), 7138-43). The role of GCS in maintaining cholesterol/glycolipid‘rafts’, cell-surface membrane domains of specialized permeability andfunctionality that appear to be involved in a variety of signaltransduction events, has also been investigated (Nature, 1997,387(6633), 569-72).

GCS is considered to be a target for treating certain human diseases.Glucosylceramide and structurally related glycolipids are stored in thelysosomes of patients with genetic diseases, which result from amutation in one of the essential glycolipid-degrading enzymes (e.g.Gaucher, Tay Sachs, Sandhoffs, GM1 gangliosidosis and Fabry diseases).Glycolipid storage also occurs as a secondary effect in some tissues(e.g. neuronal tissue) with genetic storage diseases such asNiemann-Pick C disease, mucopolysaccharidoses, mucolipidosis type IV(Proc. Natl. Acad. Sci. USA, 1998, May 26, 95(11), 6373-8) andα-mannosidosis (Proc. Natl. Acad. Sci. USA, 1991, Dec 15, 88(24),1133-04). GCS inhibitors may be applied to reduce the rate of glycolipidsynthesis in diseased cells so that there is less glycolipid present tobe stored, a treatment approach termed substrate deprivation. Studieshave demonstrated that GCS inhibitors can be used to reduce theglycolipid accumulation seen in cell and animal models of glycolipidstorage disorders (Proc. Natl. Acad. Sci. USA, 1999, 96(11), 6388-93;Science, 1997, 276(5311), 428-31; J. Clin. Invest., 2000, 105(11),1563-71). Furthermore, clinical trials have shown that GCS inhibitors,such as, N-butyldeoxynojirimycin (NB-DNJ) are useful in treating humanpatients with Gaucher disease (Lancet, 2000, 355(9214), 1481-5). The useof the imino sugar NB-DNJ as a GCS inhibitor is disclosed inEP-A-0698012. EP-A-0536402 and EP-A-0698012 disclose that N-alkylderivatives of deoxygalactonojirimycin, e.g.N-butyldeoxygalactonojirimycin (NB-DGJ), may also be of use in thetreatment of glycolipid storage disorders. EP-A-0698012 also disclosesthat the corresponding N-butyl derivatives of mannose (NB-DMJ), fucose(NB-DFJ) and N-acetylglucosamine (NB-NAG) do not act as inhibitors ofglycolipid biosynthesis.

The use of GCS inhibitors in the treatment of human malignancies hasalso been proposed. Tumours can synthesize abnormal quantities ofglycolipids that are typically present/absent in normal tissues. Inaddition glycolipids, or gangliosides, in particular are shed by tumourcells and released into the extracellular space and the bloodstream.Both tumour shed and cell surface bound tumour gangliosides caninfluence tumour host cell interactions such as cell-cell contacts oradhesion (Methods Enzymol., 2000, 312, 447-58), cell motility (Mol.Chem. Neuropathol., 1995, 24(2-3), 121-35), growth factor signallingevents (J. Biol. Chem., 2000, 275(44), 34213-23), tumour stimulatedangiogenesis (Acta. Oncol., 1997, 36(4), 383-7) and tumour specificimmune responses (J. Immunol., 1999, Oct 1, 163(7), 3718-26). All theseevents can affect tumour development and progression. Glycolipids,glucosylceramide in particular, are known to accumulate in multidrugresistant (MDR) tumour cells (Anticancer Res., 1998, 18(1B), 475-80) andin vitro treatment of these cells with GCS inhibitors can reverse theMDR phenotype (J. Biol. Chem., 1997, 272(3), 1682-7; Br. J. Cancer,1999, 81(3), 423-30).

Cell surface glycolipids also have roles in infectious disease, servingas receptors for the binding of pathogenic bacteria (APMIS, 1990, Dec,98(12), 1053-60, Review), fungi (Infect. Immun., 1990 July, 58(7),2085-90) and viruses (FEBS Lett., 1984, May 7, 170(1), 15-18). Inaddition, glycolipids on the surface of cells are bound by bacterialtoxins (Methods Enzymol., 2000, 312, 459-73) for instance, the B subunitof cholera toxin (ganglioside GM1) and verocytotoxin(globotriaosylceramide GB3) (J. Infect. Dis., 2001, suppl. 7073, 183).

GCS inhibitors may also find use in the treatment of viral infections.

The use of GCS inhibitors may also be appropriate in a number of otherclinical indications which are associated with abnormalities inglycolipid synthesis. Atherosclerotic lesions of human aorta have ahigher ganglioside content than unaffected regions of the aorta andserum ganglioside concentrations in atherosclerotic patients are higherthan in normal individuals (Lipids, 1994, 29(1), 1-5). Tissue derivedfrom the kidneys of patients with polycystic kidney disease containshigh levels of both glucosylceramide and lactosylceramide (J. Lipid.Res., 1996, Jun, 37(6), 1334-44). Renal hypertrophy in an animal modelof diabetes is associated with increases in glycolipid synthesis, (J.Clin. Invest., 1993, Mar, 91(3), 797-803).

Glycolipid metabolism also plays a critical role in neuronal disorders,such as Alzheimer's disease and epilepsy. For instance, Niemann-PickC(NPC) patient neurons present with fibrillar tangles reminiscent of themorphology seen in Alzheimer's disease.

GM1 ganglioside binding by amyloid beta-protein induces conformationalchanges that support its formation of fibrous polymers and the fibrillardeposition of this protein is an early event in Alzheimer's disease(Yanagisawa et al., 1995, Nat. Med. 1, 1062-6; Choo-Smith et al., 1997,Biol. Chem., 272, 22987-90). Thus, decreasing GM1 synthesis by usingagents such as GCS inhibitors, e.g. NB-DNJ, could inhibit the fibreformation seen in Alzheimer's disease.

In contrast, preliminary clinical trials have shown thatneurodegenerative processes seen in Parkinson's disease, stroke andspinal cord injuries seem to improve by treating patients with GM1ganglioside (Alter, (1998), Ann. NY Acad. Sci., 845, 391-4011;Schneider, 1998, Ann. NY. Acad. Sci., 845, 363-73; Geisler, (1998), Ann.NY. Acad. Sci., 845, 374-81). It is possible that co-administeringglucosylceramide synthesis inhibitors would provide the cliniciangreater control over this treatment course. GCS inhibitors like NB-DNJwould limit patient-specific inconsistencies by blocking their neuronalglycolipid synthesis. In addition, inhibiting glucosylceramide synthesiswould limit the metabolism of administered glycolipids into other,perhaps unproductive, forms. Thus, the ability to modulateglucosylceramide synthesis with GCS inhibitors may be useful in thetreatment of a wide variety of neuronal disorders.

In addition, it has also been shown that imino sugars can reversiblyinduce male sterility and can, therefore, be used as malecontraceptives. Also, GCS inhibitors could be used for the treatment ofobesity.

A role for glycolipids in some aspects of inflammatory or immuneresponses has also been suggested. Following an inflammatory stimulus,such as that obtained with thioglycolate, the ganglioside profile ofmurine peritoneal macrophages changes from a simple profile (3 majorspecies) in resting macrophage to a more complex profile (more than 14species) in activated and recruited macrophage, see Ryan, J. L. et al.,Yale J. Biol. Med., 1985, 58(2) 125-31; Yohe, H. C. et al., BiochimBiophys. Acta., 1985, 818(1), 81-6; Yohe, H. C. et al., Immunol., 1991,146(6), 1900-8. Furthermore, in vivo administration of an inflammatoryagent, e.g. bacterial endotoxin, results in the increased expression oftwo enzymes, serine palmitoyltransferase and glucosylceramide synthase,which are key to the de novo synthesis of glycolipids, see Memon, R. A.et al., J. Biol. Chem., 1999, 274(28), 19707-13; Memon, R. A. et al., J.Lipid. Res., 2001, 42(3), 452-9.

Such a role for glycolipids is further supported by the demonstration ofchanges in glycolipid expression in animals with genetic defects whichresult in hyper- or hypo-sensitive responses to inflammatory stimuli.For example, upon endotoxin treatment in C3H/HeJ mice, which have atoll-like receptor 4 mutation and are hypo-responsive to bacterialendotoxin, recruited macrophages were found to lack ganglioside G_(M1b),which is a major ganglioside found in recruited macrophages in normalmice, see Yohe, H. C. et al., Immunol., 1991, 146(6), 1900-8; Yohe, H.C. et al., Immunol., 1986, 137(12), 3921-7.

Hence, GCS inhibitors may be useful in the treatment of inflammatorydiseases and other disorders associated with macrophage recruitment andactivation, including but not limited to, rheumatoid arthritis, Crohn'sdisease, asthma and sepsis.

WO02/055498, published after the priority date of the presentapplication, discloses piperidine derivatives useful as GCS inhibitors.

Given the importance of GCS in a wide spectrum of diseases, it isessential that new tools that provide a means for modulating thisenzyme's function be developed. Towards this end, we have identified aclass of novel compounds that are useful in inhibiting GCS's catalyticactivity.

The compounds of the invention may exhibit improved potency and/orselectivity for GCS, relative to non-lysosomal-β-glucocerebrosidaseactivity, over known hydroxylated piperidine derivatives.

According to the invention there is provided a compound of formula (I)or a pharmaceutically acceptable salt or prodrug thereof:

wherein

R is C₁₋₃ alkylAr¹ where Ar¹ is phenyl or pyridyl;

wherein phenyl is substituted by one or more substituents selected fromCN, CON(R¹)₂, SO_(n)R₂, SO₂N(R¹)₂, N(R⁵)₂, N(R¹)COR², N(R¹)SO_(n)R²,C₀₋₆ alkylAr², C₂₋₆ alkenylAr² and C₃₋₆ alkynylAr² wherein one or moreof the —CH₂— groups of the alkyl chain may be replaced with a heteroatomselected from O, S and NR³, provided that when the heteroatom is O, atleast two —CH₂— groups separate it from any additional O atom in thealkyl chain; or two adjacent substituents on the Ar¹ phenyl may togetherform a fused 5- or 6-membered saturated or unsaturated ring wherein thering optionally contains 1 or 2 heteroatoms selected from O, S and NR⁴and is optionally substituted by one or more substituents selected from,an oxo group, C₁₋₆ alkyl and C₀₋₃ alkylAr⁴;

and the Ar¹ phenyl is optionally substituted by one or more additionalsubstituents selected from F, Cl, Br, CF₃, OCF₃, OR³ and C₁₋₆ alkyl;

and wherein pyridyl is substituted by one or more substituents, selectedfrom, CN, CON(R¹)₂, SO_(n)R², SO₂N(R¹)₂, N(R⁵)₂, N(R¹)COR²,N(R¹)SO_(n)R², F, Cl, Br, CF₃, OCF₃, OR³, C₁₋₆ alkyl, C₀₋₆ alkylAr²,C₂₋₆ alkenylAr² and C₃₋₆ alkynylAr² wherein one of the —CH₂— groups ofthe alkyl chain may be replaced with a heteroatom selected from O, S andNR³, provided that when the heteroatom is O, at least two —CH₂— groupsseparate it from any additional O atom in the alkyl chain; or twoadjacent substituents on the Ar¹ pyridyl may together form a fused 5- or6-membered saturated or unsaturated ring wherein the ring optionallycontains 1 or 2 heteroatoms selected from O, S and NR⁴ and is optionallysubstituted by one or more substituents selected from, an oxo group,C₁₋₆ alkyl and C₀₋₃ alkylAr⁴;

R¹ is H, C₁₋₆ alkyl optionally substituted by OH, Ar³, or C₁₋₆ alkylAr³,or the group N(R¹)₂ may form a 5- to 10-membered heterocyclic groupoptionally containing one or more additional heteroatoms selected fromO, S and NR³ and is optionally substituted by an oxo group;

R² is C₁₋₆alkyl optionally substituted by OH, Ar³, or C₁₋₆ alkylAr³;

R³ is H, or C₁₋₆ alkyl;

R⁴ is H, C₁₋₆ alkyl or C₀₋₃ alkylAr⁴;

R⁵ is H, C₁₋₆ alkyl optionally substituted by OH, Ar³ or C₁₋₆ alkylAr¹,or the group N(R⁵)₂ may form a 5- to 10-membered heterocylic groupoptionally containing one or more additional heteroatoms selected fromO, S and NR³ and is optionally substituted by an oxo group;

Ar² and Ar³ are independently phenyl or a 5- to 10-membered heteroarylgroup containing up to 3 heteroatoms selected from O, S and NR³, whichmay be optionally substituted by one or more substituents selected fromF, Cl, Br, CN, CF₃, OCF₃, OR³ and C₁₋₆ alkyl;

Ar⁴ is phenyl or pyridyl either of which may be optionally substitutedby one or more substituents selected from F, Cl, Br, CN, CF₃, OCF₃, OR³and C₁₋₆ alkyl; and

n is 0, 1 or 2.

R is preferably C₁ alkyLAr¹.

Ar¹ is preferably phenyl, wherein phenyl is substituted as defined forformula (I).

Ar¹ phenyl is preferably substituted on the para position.

More preferably Ar¹ is phenyl, wherein phenyl is substituted by one ormore substituents selected from CN, CON(R¹)₂, SO₂N(R⁵)₂, N(R¹)₂,N(R¹)COR², C₀₋₆ alkylAr² and C₂₋₆ alkenylAr² wherein one or more of the—CH₂— groups of the alkyl chain may be replaced with a heteroatomselected from O, S and NR³, provided that when the heteroatom is O, atleast two —CH₂— groups separate it from any additional O atom in thealkyl chain; or two adjacent substituents on the Ar¹ phenyl may togetherform a fused 5- or 6 membered saturated or unsaturated ring wherein thering optionally contains 1 or 2 heteroatoms selected from O and NR⁴ andis optionally substituted by one or more substituents selected from, anoxo group, C₁₋₆ alkyl and C₀₋₃ alkyl⁴, and the Ar¹ is optionallysubstituted by one or more additional substituents selected from F, Cl,Br, CF₃, OCF₃, OR³ and C₁₋₆ alkyl.

Yet more preferably Ar¹ is phenyl, wherein phenyl is substituted by oneor more substituents selected from CN, CON(R¹)₂, N(R⁵)₂ and C₀₋₆alkylAr² wherein one or more of the —CH₂— groups of the alkyl chain maybe replaced with a heteroatom selected from O, S and NR³, provided thatwhen the heteroatom is O, at least two —CH₂— groups separate it from anyadditional O atom in the alkyl chain; or two adjacent substituents onthe Ar¹ phenyl may together form a fused 5- or 6-membered saturated orunsaturated ring wherein the ring optionally contains 1 or 2 heteroatomsselected from O and NR⁴ and is optionally substituted by one or moresubstituents selected from, an oxo group, C₁₋₆ alkyl and C₀₋₃ alkylAr⁴,and the Ar¹ is optionally substituted by one or more additionalsubstituents selected from F, Cl, Br, CF₃, OCF₃, OR³ and C₁₋₆ allyl.

Even more preferably Ar¹ is phenyl, wherein phenyl is substituted by oneor more substituents selected from CN, CON(R¹)₂, N(R⁵)₂ and C₀₋₆alkylAr¹ wherein one or more of the —CH₂— groups of the alkyl chain maybe replaced with O, provided that at least two —CH₂— groups separate itfrom any additional O atom introduced into the alkyl chain, and the Ar¹phenyl is optionally substituted by one or more additional substituentsselected from F, Cl, Br, CF₃, OCF₃, OR³ and C₁₋₆ alkyl.

When Ar¹ is phenyl and has an additional optional substitutent asdefined for formula (I) on the ortho position, the substituent ispreferably selected from OCH₃ and F. More preferably the orthosubstituent is F.

When Ar¹ is phenyl substituted by C₂ alkylAr² wherein one of the —CH₂—groups of the alkyl chain is replaced with O, preferably, the —CH₂—group linked to the Ar¹ phenyl is replaced with O.

R¹ is preferably H, C₁₋₆ alkyl or C₁₋₆ alkylAr³. More preferably R¹ is Hor C₁₋₆ alkylAr³.

R² is preferably Ar³ or Can alkylAr³. More preferably R² is C₁₋₆alkylAr³.

R³ is preferably H.

R⁴ is preferably H or C₁₋₆ alkyl. More preferably R⁴ is H.

R⁵ is preferably C₁₋₆ alkyl optionally substituted by OH, or C₁₋₆alkyLAr³. More preferably R⁵ is C₁₋₆ alkyl.

For the groups R¹, R² or R⁵, the group C₁₋₆ alkylAr³ is preferably C₁₋₃alkylAr³, for example, C₁ alkylAr³ or C₂ alkylAr₂.

Ar² is preferably phenyl which may be optionally substituted by one ormore substituents selected from F, Cl, Br, CN, CF₃, OCF₃, OR³ and C₁₋₆alkyl.

Ar³ is preferably phenyl which may be optionally substituted by one ormore substituents selected from F, Cl, Br, CN, CF₃, OCF₃, OR³ and C₁₋₆alkyl.

Ar⁴ is preferably phenyl which may be optionally substituted by one ormore substituents selected from F, Cl, Br, CN, CF₃, OCF₃, OR³ and C₁₋₆alkyl.

n is preferably 2.

In the groups CON(R¹)₂, SO₂N(R¹)₂, and N(R⁵)₂ the R¹ and R⁵ groups maybe the same or different.

When two adjacent substituents on the Ar¹ form a fused 5- or 6-memberedsaturated or unsaturated ring optionally containing 1 or 2 heteroatomsselected from O, S and NR⁴, examples of bicyclic groups which may beformed include benzofuran, indole, benzoxazine, quinoline andisoquinoline.

When N(R¹)₂ forms a 5- to 10-membered heterocyclic group optionallycontaining one or more additional heteroatoms selected from O, S andNR³, examples of heterocyclic groups include, piperidine, piperizine,morpholine and quinoline.

When N(5)₂ forms a 5- to 10 membered heterocyclic group, preferably a 5-or 6-membered heterocyclic group, optionally containing one or moreadditional heteroatoms selected from O, S and NR³, examples ofheterocyclic groups include, piperidine, piperizine and morpholine.

When Ar² or Ar³ is a 5- to 10-membered heteroaryl group, examples ofheteroaryl groups include furan, thiophene, oxazole, triazole, pyridine,pyrazine, pyrimidine, benzofuran benzothiophene and benzoxazine.

A specific group of compounds of formula (I) which may be mentioned arethose where R is C₁₋₆ alkylaryl where aryl is phenyl or pyridyl;

wherein phenyl is substituted by one or more substituents selected fromCN, CON(R¹)₂, SO₂R², N(R²)₂, and N(R¹)COR², or two adjacent substituentson the phenyl may together form a fused 5- or 6-membered saturated orunsaturated ring optionally containing 1 or 2 heteroatoms, selected fromN and O, and the phenyl is optionally substituted by one or moreadditional substituents selected from F, Cl, Br, CF₃, OCF₃, and OR¹;

and wherein pyridyl is substituted by one or more substituents, selectedfrom, CN, CON(R¹)₂, SO₂R², N(R²)₂, N(R¹)COR², F, Cl, Br, CF₃, OCF₃, andOR¹ or two adjacent substituents on the pyridyl may together form afused 5- or 6-membered saturated or unsaturated ring which mayoptionally contain 1 or 2 heteroatoms, selected from N and 0;

R¹ is H, or C₁₋₆ alkyl; and

R² is C₁₋₆ alkyl.

Another specific group of compounds of formula (I) that may be mentionedare those where R is C₁₋₃ alkylAr¹ where Ar¹ is phenyl or pyridyl;

wherein phenyl is substituted by one or more substituents selected fromCN, CON(R¹)₂, SO₂R², N(R²)₂, N(R¹)COR², and C₁₋₃ alkylAr² wherein one ofthe —CH₂— groups of the alkyl chain may be replaced with O and where Ar²is phenyl or a 5- or 6-membered heteroaryl group containing up to 3heteroatoms selected from N, O and S; or two adjacent substituents onthe Ar¹ phenyl may together form a fused 5- or 6-membered saturated orunsaturated ring optionally containing 1 or 2 heteroatoms selected fromN and O;

and wherein pyridyl is substituted by one or more substituents, selectedfrom, CN, CON(R¹)₂, SO₂R², N(R²)₂, N(R¹)COR², F, Cl, Br, CF₃, OCF₃, OR³,and C₁₋₃ allylAr² wherein one of the —CH₂— groups of the alkyl chain maybe replaced with O and where Ar² is phenyl or a 5- or 6-memberedheteroaryl group containing up to 3 heteroatoms selected from N, O andS; or two adjacent substituents on the pyridyl may together form a fused5- or 6-membered saturated or unsaturated ring optionally containing 1or 2 heteroatoms selected from N and O;

and the Ar¹ or Ar² phenyl is optionally substituted by one or moreadditional substituents selected from F, Cl, Br, CF₃, OCF₃, and OR³;

R¹ is H, C₁₋₆ alkyl, Ar³, or C₁₋₆ alkylAr³ where Ar³ is phenyl or a 5-or 6-membered heteroaryl group containing up to 3 heteroatoms selectedfrom N, O and S, any of which may be substituted by one or moresubstituents selected from F, Cl, Br, CF₃, OCF₃, and OR³;

R² is C₁₋₆ alkyl, Ar³, or C₁₋₆ alkylAr³ where Ar³ is phenyl or a 5- or6-membered heteroaryl group containing up to 3 heteroatoms selected fromN, O and S, any of which may be substituted by one or more substituentsselected from F, Cl, Br, CF₃, OCF₃, and OR³; and

R³ is H, or C₁₋₆ alkyl.

Yet another specific group of compounds of formula (I) that may bementioned are those where

R is C₁₋₃ alkylAr¹ where Ar¹ is phenyl or pyridyl;

wherein phenyl is substituted by one or more substituents selected fromCN, CON(R¹)₂, SO_(n)R², SO₂N(R¹)₂, N(R²)₂, N(R¹)COR², N(R¹)SO_(n)R²,C₀₋₆ alkylAr², C₂₋₆ alkenylAr² and C₃₋₆ alkynylAr² wherein one or moreof the —CH₂— groups of the alkyl chain may be replaced with a heteroatomselected from O, S and NR³, provided that when the heteroatom is O, atleast two —CH₂— groups separate it from any additional O atom in thealkyl chain; or two adjacent substituents on the Ar¹ phenyl may togetherform a fused 5- or 6-membered saturated or unsaturated ring wherein thering optionally contains 1 or 2 heteroatoms selected from O and NR⁴ andis optionally substituted by one or more substituents selected f from,an oxo group, C₁₋₆ alkyl and C₀₋₃ allkyAr⁴;

and the Ar¹ phenyl is optionally substituted by one or more additionalsubstituents selected from F, Cl, Br, CF₃, OCF₃, OR³ and C₁₋₆ alkyl;

and wherein pyridyl is substituted by one or more substituents, selectedfrom, CN, CON(R¹)₂, SO_(n)R², SO₂N(R¹)₂, N(R²)₂, N(R¹)COR²,N(R¹)SO_(n)R², F, Cl, Br, CF₃, OCF₃, OR³, C₁₋₆ alkyl, C₀₋₆ alkylAr²,C₂₋₆ alkenylAr² and C₃₋₆ alkynylAr² wherein one of the —CH₂— groups ofthe alkyl chain may be replaced with a heteroatom selected from O, S andNR³, provided that when the heteroatom is O, at least two —CH₂— groupsseparate it from any additional O atom in the alkyl chain; or twoadjacent substituents on the Ar¹ pyridyl may together form a fused 5- or6-membered saturated or unsaturated ring wherein the ring optionallycontains 1 or 2 heteroatoms selected from O and NR⁴ and is optionallysubstituted by one or more substituents selected from, an oxo group,C₁₋₆ alkyl and C₀₋₃ aLIylAr⁴;

R¹ is H, C₁₋₆ alkyl, Ar³, or C₁₋₆ alkylAr³, or the group N(R¹)₂ may forma 5- to 10 membered heterocyclic group optionally containing one or moreadditional heteroatorns selected from O and NR³;

R² is C₁₋₆ alkyl, Ar³, or C₁₋₆ alkylAr³, or the group N(R²)₂ may form a5- to 6-membered heterocylic group optionally containing one or moreadditional heteroatoms selected from O and NR³ and is optionallysubstituted by an oxo group;

R³ is H, or C₁₋₆ alkyl;

R⁴ is H, C₁₋₆ alkyl or C₀₋₃ alkylAr⁴;

Ar² is phenyl or a 5- or 6-membered heteroaryl group containing up to 3heteroatoms selected from O, S and NR³, any of which may be optionallysubstituted by one or more substituents selected from F, Cl, Br, CN,CF₃, OCF₃, OR³ and C₃₋₄ alkyl;

Ar³ is phenyl or a 5- to 10 membered heteroaryl group containing up to 3heteroatoms selected from O, S and NR³, any of which may be optionallysubstituted by one or more substituents selected from F, Cl, Br, CN,CF₃, OCF₃, OR³ and C₁₋₆ alkyl;

Ar⁴ is phenyl or pyridyl either of which may be optionally substitutedby one or more substituents selected from F, Cl, Br, CN, CF₃, OCF₃, OR³and C₁₋₆ alkyl; and

n is 0, 1 or 2.

The compounds of the invention preferably have a molecular weight ofless than 800, more preferably less than 600.

The term “alkyl” as used herein whether on its own or as part of alarger group e.g. “alkylaryl”, includes both straight and branched chainradicals. The term alkyl also includes those radicals wherein one ormore hydrogen atoms are replaced by fluorine. Alkenyl and alkynyl are tobe interpreted accordingly.

The term “heterocyclic group” as used herein includes, unless otherwisedefined, non-aromatic and aromatic, single and fused, rings containingone or more, e.g. up to three, heteroatoms in each ring, each of whichis selected from O, S and N, which rings, may be unsubstituted orsubstituted. Each heterocyclic ring suitably has from 5 to 10,preferably 5, 6, 9 or 10 ring atoms. A fused heterocyclic ring systemmay include carbocyclic rings and need include only one heterocyclicring. Examples of heterocyclyl groups, including heteroaromatic ringsystems, are as follows: pyrrolidine, piperidine, piperazine,morpholine, imidazolidine, pyrazolidine, pyrrole, quinoline,isoquinoline, pyridine, pyrazine, pyrimidine, oxazole, thiazole,thiophene, indole, furan, thiadiazole, triazole, imidazole, benzopyran,benzofuran, benzothiophene, benzoxazine and benzamidazole. “Heteroaryl”is to be interpreted accordingly.

Specific compounds of the invention include the compounds provided inthe Examples and pharmaceutically acceptable salts and prodrugs thereof.

Preferred compounds of the invention include:

-   Benzamide,    N-[(4-fluorophenyl)methyl]-4-[[(2S,3S,4R,5S)-3,4,5-trihydroxy-2-hydroxymethyl)-1-piperidinyl]methyl]-,-   3,4,5-Piperidinetriol,    2-(hydroxymethyl)-1-[[4-(phenylmethoxy)phenyl]methyl]-,    (2S,3S,4R,5S),-   Benzamide,    N-[1-(R)-(phenyl)ethyl]-4-[[(2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-;-   3,4,5-Piperidinetriol,    1-[(3-cyano-4-dipropylamino)phenyl)methyl]-2-(hydroxoymethyl)-,    (2S,3S,4R,5S),-   Benzamide,    N-[1-(S)-4-fluorophenyl)ethyl]-4-[[(2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-,-   Benzamide,    N-[1-(R)-(4-fluorophenyl)ethyl]4-[[(2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-;-   3,4,5-Piperidinetriol,    2-(hydroxymethyl)-1-[(2-phenyl-2H-1,4-benzoxazin-3(4H)-one-6-yl)methyl]-,    (2S,3S,4R,5S) and pharmaceutically acceptable salts and prodrugs    thereof.

A highly preferred compound of the invention is:

-   3,4,5-Piperidinetriol,    2-hydroxymethyl)-1-[[4-(phenylmethoxy)phenyl]methyl]-, (2S,3S,4R,5S)    and pharmaceutically acceptable salts and prodrugs thereof.

As described herein, for all aspects of the invention, reference tocompounds of formula (I) encompasses pharmaceutically acceptable saltsand prodrugs thereof.

As described herein, the compounds of the present invention can be usedfor the inhibition of GCS. Thus, an aspect of the present inventionprovides the use of the compounds of formula (I) in medicine.

Suitable, pharmaceutically acceptable salts of the compounds of formula(I) include, but are not limited to, salts with inorganic acids such ashydrochloride, sulfate, phosphate, diphosphate, hydrobromide andnitrate, or salts with an organic acid such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, palmitate, salicylate andstearate.

Suitable prodrugs of the compounds of formula (I) include, but are notlimited to, pharmaceutically acceptable esters such as C₁₋₆ alkylesters.

Some of the compounds of this invention may be crystallised orrecrystallised from solvents such as aqueous and organic solvents. Insuch cases solvates may be formed. This invention includes within itsscope stoichiometric solvates including hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation.

Certain of the R groups of compounds of formula (I) may exist in theform of optical isomers, e.g. diastereoisomers and mixtures of isomersin all ratios, e.g. racemic mixtures. The invention includes all suchforms, in particular the pure isomeric forms. The different isomericforms may be separated or resolved one from the other by conventionalmethods, or any given isomer may be obtained by conventional syntheticmethods or by stereospecific or asymmetric syntheses.

The compounds of the invention may exist as tautomers, e.g. keto/enoltautomers, all of which are included within the scope of formula (I).

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they arepreferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75% pure and preferably at least 85%,especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5%, e.g. 10 to 59%, of a compound of formula (I) orpharmaceutically acceptable derivative thereof.

The compounds of formula (I) can be prepared by art-recognizedprocedures from known or commercially available starting materials. Ifthe starting materials are unavailable from a commercial source, theirsynthesis is described herein, or they can be prepared by proceduresknown in the art.

Specifically, the compounds of formula (I) may be prepared by processescomprising:a) reductive amination of an aldehyde of formula R⁵CHO wherein R⁵ isC₀₋₂ alkylAr¹ where Ar¹ is as defined in formula (I) with a compound offormula (II):

the reductive amination may be perfomed by methods known to thoseskilled in the art, e.g. using NaBH3CN or a supported reagent such as(polystyrylmethyl) trimethylammonium cyanoborohydride in aceticacid-methanol or HCl-methanol, or using NaBH(OAc)₃ in a solvent, such asdichloromethane; orb) deprotection of a compound of formula (III):

wherein R is as defined in formula (I) and P, which may be the same ordifferent, are hydroxy protecting groups e.g. benzyl or substitutedbenzyl. When P is benzyl or substituted benzyl the deprotection ispreferably conducted in the presence of hydrogen gas and a catalyst,such as, PdCl₂ or palladium on carbon in a suitable solvent, such as, analcohol, e.g. ethanol. It will be understood that when P is benzyl orsubstituted benzyl and R is substituted benzyl, the R group can also beremoved under these conditions to give compounds of formula (II). Thus,compounds of formula (I) where R is substituted benzyl are preferablyproduced using process a) above.

The compound of formula (II) is known, see e.g. Tet. Lett., 1997,38(45), 8009-12.

Compounds of formula (III) may be prepared by reacting a compound offormula (I):

wherein OL, which may be the same or different are leaving groups, suchas mesyloxy, and P is as defined for formula (III), with an amine offormula RNH₂, wherein R is as defined in formula (I), either neat or ina solvent such as tetrahydrofuran.

Compound (IVa), wherein L is mesyl and P is benzyl, may be prepared byreacting 2,3,4,6-tetra-O-benzyl-D-galactitol with mesyl chloride in thepresence of a base such as pyridine, as described in WO02/055498.

Any novel intermediate compounds as described herein also fall withinthe scope of the present invention. Thus according to a further aspectof the invention there is provided a compound of formula (III) asdefined above.

The invention also provides a compound of formula (I) when producedaccording to the methods described above.

During the synthesis of the compounds of formula (I) labile functionalgroups in the intermediate compounds, e.g. hydroxy, carboxy and aminogroups, may be protected. A comprehensive discussion of the ways inwhich various labile functional groups may be protected and methods forcleaving the resulting protected derivatives is given in for exampleProtective Groups in Organic Chenmistry, T. W. Greene and P. G. M. Wuts,(Wiley-Interscience, New York, 2nd edition, 1991).

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 500 compounds and morepreferably 10 to 100 compounds of formula (I). Libraries of compounds offormula (I) may be prepared by multiple parallel synthesis using eithersolution phase or solid phase chemistry, by procedures known to thoseskilled in the art.

Thus according to a further aspect of the invention there is provided acompound library comprising at least 2 compounds of formula (I) orpharmaceutically acceptable salts or prodrugs thereof.

The pharmaceutically acceptable salts and prodrugs of the compounds offormula (I) may be prepared by methods well known to those skilled inthe art.

The pharmaceutically effective compounds of formula (I) may beadministered in conventional dosage forms prepared by combining acompound of formula (I) (“active ingredient”) with standardpharmaceutical carriers, excipients or diluents according toconventional procedures well known in the art. These procedures mayinvolve mixing, granulating and compressing or dissolving theingredients as appropriate to the desired preparation.

According to a further aspect, the present invention provides apharmaceutical composition comprising a compound of formula (I),together with one or more pharmaceutically acceptable carriers,excipients and/or diluents.

The active ingredient or pharmaceutical composition can be administeredsimultaneously, separately or sequentially with another treatment forthe disorder to be treated.

The active ingredient or pharmaceutical composition may be administeredto a subject by any of the routes conventionally used for drugadministration, for example they may be adapted for oral (includingbuccal, sublingual), topical (including transdermal), nasal (includinginhalation), rectal, vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) administration to mammalsincluding humans. The most suitable route for administration in anygiven case will depend on the particular compound or pharmaceuticalcomposition, the subject and the nature and severity of the disease andthe physical condition of the subject. Such compositions may be preparedby any method known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s), excipient(s)and/or diluent(s).

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Tablets and capsules for oral administration may be in unit dosepresentation form and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulfate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, impregnated dressings, sprays, aerosols or oilsand may contain appropriate conventional additives such aspreservatives, solvents to assist drug penetration and emollients inointments and creams. Such applications include those to the eye orother external tissues, for example the mouth and skin and thecompositions are preferably applied as a topical ointment or cream. Whenformulated in an ointment, the active ingredient may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredient may be formulated in a cream with an oil-in-watercream base or a water-in-oil base. The composition may also containcompatible conventional carriers, such as cream or ointment bases andethanol or oleyl alcohol for lotions.

Pharmaceutical compositions adapted for topical administration to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical compositions adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318, (1986).

Pharmaceutical compositions adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered by rapidinhalation through the nasal passage from a container of the powder heldclose up to the nose. Suitable compositions wherein the carrier is aliquid, for administration as a nasal spray or as nasal drops, includeaqueous or oil solutions of the active ingredient.

Pharmaceutical compositions adapted for administration by inhalationinclude fine particle dusts or mists which may be generated by means ofvarious types of metered dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical compositions adapted for rectal administration may bepresented as suppositories or enemas. Suppositories will containconventional suppository bases, e.g. cocoa-butter or other glyceride;

Pharmaceutical compositions adapted for vaginal administration may bepresented as pessaries, tampons, creams; gels, pastes, foams or spraycompositions.

Pharmaceutical compositions adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials and may be stored in a freeze-dried (lyophilieed) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

For parenteral administration, fluid unit dosage forms are preparedutilizing the active ingredient and a sterile vehicle, e.g. water. Theactive ingredient, depending on the vehicle and concentration used, canbe either suspended or dissolved in the vehicle. In preparing solutionsthe active ingredient can be dissolved in water for injection and filtersterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance stability,the composition can be frozen after filling into the vial and the waterremoved under vacuum. The dry lyophilized powder is then sealed in thevial and an accompanying vial of water for injection may be supplied toreconstitute the liquid prior to use. Parenteral suspensions areprepared in substantially the same manner except that the activeingredient is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The activeingredient can be sterilised by exposure to ethylene oxide beforesuspending in the sterile vehicle.

Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the active ingredient.

The pharmaceutical compositions according to the invention arepreferably adapted for oral administration.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions may also include other agentsconventional in the art having regard to the type of formulation inquestion, for example those suitable for oral administration may includeflavouring agents. They may also contain therapeutically active agentsin addition'to the compounds of the present invention. Such carriers maybe present as from about 1% up to about 98% of the formulation. Moreusually they will form up to about 80% of the formulation.

The compositions may contain from 0.1% by weight, e.g. 10-60% by weight,of the active material, depending on the method of administration.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per dose. Such aunit may contain for example 0.1 mg/kg to 750 mg/kg, more preferably 0.1mg/kg to 10 mg/kg depending on the condition being treated, the route ofadministration and the age, weight and condition of the patient.Preferred unit dosage compositions are those containing a daily dose orsub-dose, or an appropriate fraction thereof, of an active ingredient.

It will be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of active ingredients will bedetermined by the nature and extent of the condition being treated, theform, route and site of administration and the particular subject beingtreated and that such optimums can be determined by conventionaltechniques. It will also be appreciated by one of skill in the art thatthe optimal course of treatment, i.e. the number of doses of the activeingredients given per day for a defined number of days, can beascertained by those skilled in the art using conventional course oftreatment determination tests.

No toxicological effects are indicated when the compounds of formula (I)are administered in the above mentioned dosage range.

The compounds of the invention are useful in that they are capable ofinhibiting glucosylceramide synthase. Thus, the compounds of theinvention can be used in the treatment of various glycolipid storagediseases, such as, Gaucher's disease, Sandhoffs disease, Tay-Sachsdisease, Fabry disease, GM1 gangliosidosis etc. In addition, compounds,such as, this also can find use in the treatment of conditions in whichglycolipid accumulation occurs, such as, Niemann-Pick disease,mucopolysaccharidoses (MPS I, MPS IIIA, MPS IIIB, MPS VI and MPS VII,preferably MPS I), mucolipidosis type IV and α-mannosidosis.

The compounds of the present invention can also be used in the treatmentof cancers in which glycolipid synthesis is abnormal, such as, braintumours, neuroblastoma, malignant melanoma, renal adenocarcinoma andmulti-drug resistant cancers in general.

The compounds of the present invention can also be used in the treatmentof diseases caused by infectious organisms which use cell surfaceglycolipids as receptors for either the infectious organism itself orfor a toxin produced by the infectious organism (e.g. for attachmentand/or invasion onto/into the host cell).

The compounds of the present invention may also be used in the treatmentof diseases caused by infectious organisms for which the synthesis ofglucosylceramide is an essential or important process, such as,pathogenic fungi, e.g. Cryptococcus neofonnans or viral infections, e.g.viruses that require host cell enzymes to synthesize and properly foldtheir viral envelope glycoproteins, or viruses that acquire a componentof their envelope from an internal host cell membrane. GCS inhibitionmay result in improper glycoprocessing or the misfolding of one or moreviral envelope glycoproteins, inhibition of viral secretion, or improperviral fusion of the virus with its target cells. Suitable viralinfections for treatment may be caused by, for example but not limitedto, the following viruses: flaviviruses and pestiviruses, e.g. hepatitisC virus, yellow fever virus, dengue viruses 14, Japanese encephalitisvirus, Murray Valley encephalitis virus, Rocio virus, West Nile fevervirus, St. Louis encephalitis virus, tick-borne encephalitis virus,Louping ill virus, Powassan virus, Omsk hemorrhagic fever virus, andKyasanur forest disease virus; hepadnavirus, e.g. hepatitis B virus;paramyxovirus, e.g. respiratory syncytial virus or retroviruses, suchas, human immunodeficiency virus.

The compounds of the present invention can also be used in the treatmentof diseases in which excessive glycolipid synthesis occurs, such as, butnot limited to, atherosclerosis, polycystic kidney disease and diabeticrenal hypertrophy.

The compounds of the present invention can also be used in the treatmentof neuronal disorders, such as, Alzheimer's disease or epilepsy; andneuronal degenerative diseases, such as, Parkinsons' disease.

The compounds of the present invention can also be used in the treatmentof neuronal injury, such as, spinal cord injuries or stroke.

The compounds of the present invention can also be used for reversiblyrendering a male mammal infertile.

The compounds of the present invention can also be used in the treatmentof obesity.

The compounds of the present invention can also be used in the treatmentof inflammatory diseases or disorders associated with macrophagerecruitment and activation, including but not limited to, rheumatoidarthritis, Crohn's disease, asthma and sepsis.

In additional aspects, therefore, the present invention provides:

(i) the use of a compound of formula (I) in the manufacture of amedicament for use as an inhibitor of glucosylceramide synthase.

(ii) the use of a compound of formula (I) in the manufacture of amedicament for the treatment of a glycolipid storage disease. Examplesof glycolipid storage disease which can be treated include, but are notlimited to, Gaucher disease, Sandhoffs disease, Tay-Sachs disease, Fabrydisease or GM1 gangliosidosis.

(iii) the use of a compound of formula (I) in the manufacture of amedicament for the treatment of Niemann-Pick disease, types A and C.

(iv) the use of a compound of formula (I) in the manufacture of amedicament for the treatment of mucopolysaccharidosis type I,mucopolysaccharidosis type IIA, mucopolysaccharidosis type IIIB,mucopolysaccharidosis type VI or mucopolysaccharidosis type VII.Preferably the compounds are used in the treatment ofmucopolysaccharidosis type I.

(v) the use of a compound of formula (I) in the manufacture of amedicament for the treatment of α-mannosidosis or mucolipidosis type IV.

(vi) the use of a compound of formula (I) in the manufacture of amedicament for the treatment of cancer in which glycolipid synthesis isabnormal, including but not limited to brain cancer, neuronal cancer,neuroblastoma, renal adenocarcinoma, malignant melanoma, multiplemyeloma and multi-drug resistant cancers.

(vii) the use of a compound of formula (I) in the manufacture of amedicament for use in the treatment of Alzheimer's disease, epilepsy orstroke.

(viii) the use of a compound of formula (a) in the manufacture of amedicament for use in the treatment of Parkinson's disease.

(ix) the use of the compound of formula (I) in the manufacture of amedicament in the treatment of spinal injury.

(x) the use of a compound of formula (I) in the manufacture of amedicament for use in the treatment of diseases caused by infectiousmicroorganisms which utilize glycolipids on the surface of cells asreceptors for either the organism itself or for toxins produced by theorganism.

(xi) the use of a compound of formula (I) in the manufacture of amedicament for use in the treatment of disease caused by infectiousorganisms for which the synthesis of glucosylceramide is an essential orimportant process, such as but not limited to, pathologies associatedwith infections of pathogenic fungi, e.g. Cryptococcus neoformans orpathologies associated with viral infections.

(xii) the use of a compound of formula (I) in the manufacture of amedicament for use in the treatment of diseases associated with abnormalglycolipid synthesis, including but not limited to, polycystic kidneydisease, diabetic renal hypertrophy and atherosclerosis.

(xiii) the use of a compound of formula (I) in the manufacture of amedicament for the treatment of a condition treatable by theadministration of a ganglioside, such as GM1 ganglioside. Examples ofsuch conditions are Parkinson's disease, stroke and spinal cordinjuries.

(xiv) the use of a compound of formula (I) in the manufacture of amedicament for reversibly rendering a male mammal infertile.

(xv) the use of a compound of formula (I) in the manufacture of amedicament for the treatment of obesity, e.g. as an appetitesuppressant.

(xvi) the use of a compound of formula (I) in the manufacture of amedicament for the treatment of inflammatory diseases or disordersassociated with macrophage recruitment and activation, including but notlimited to, rheumatoid arthritis, Crohn's disease, asthma and sepsis.

(xvii) a method for the treatment of a glycolipid storage disease, e.g.Gaucher's disease, Sandhoffs disease, Tay-Sachs disease or GM1gangliosidosis, which comprises the step of administering to a patientan effective amount of a compound of formula (I).

(xviii) a method for the treatment of Niemann-Pick disease, types A andC, which comprises the step of administering to a patient an effectiveamount of a compound of formula (I).

(xix) a method for the treatment of mucopolysaccharidosis type I,mucopolysaccharidosis type IIIA, mucopolysaccharidosis type IIIB,mucopolysaccharidosis type VI or mucopolysaccharidosis type VII whichcomprises the step of administering to a patient an effective amount ofa compound of formula (I).

(xx) a method for the treatment of α-mannosidosis or mucolipidosis typeIV which comprises the step of administering to a patient an effectiveamount of a compound of formula (I).

(xxi) a method for the treatment of cancer in which glycolipid synthesisis abnormal, including but not limited to brain cancer, neuronal cancer,renal adenocarcinoma, malignant melanoma, multiple myeloma andmulti-drug resistant cancers, which comprises the step of administeringto a patient an effective amount of a compound of formula (I).

(xxii) a method for the treatment of Alzheimer's disease, epilepsy orstroke which comprises the(step of administering to a patient aneffective amount of a compound of formula (I).

(xxiii) a method for the treatment of Parkinson's disease, whichcomprises the step of administering to a patient an effective amount ofa compound of formula (I).

(xxiv) a method for the treatment of spinal injury which comprises thestep of administering to a patient an effective amount of a compound offormula (I).

(xxv) a method for the treatment of diseases caused by infectiousmicroorganisms, which utilize glycolipids on the surface of cells asreceptors for either the organism itself or for toxins produced by theorganism, which comprises the step of administering to a patient aneffective amount of a compound of formula (I).

(xxvi) a method for the treatment of diseases caused by infectiousorganisms, e.g. pathogenic fungi or viruses, for which the synthesis ofglucosylceramide is an essential or important process, such as but notlimited to, pathologies associated with Cryptococcus neoformansinfection, or pathologies associated with viral infections, whichcomprises the step of administering to a patient an effective amount ofa compound of formula (I).

(xxvii) a method for the treatment of diseases associated with abnormalglycolipid synthesis including but not limited to polycystic kidneydisease, diabetic renal hypertrophy and atherosclerosis, which comprisesthe step of administering to a patient an effective amount of a compoundof formula (I).

(xxviii) a method for the treatment of a condition treatable by theadministration of a ganglioside, such as GM1 ganglioside, whichcomprises the step of administering to a patient an effective amount ofa compound of formula (I). Examples of such conditions are, Parkinson'sdisease, stroke and spinal cord injuries.

(xxix) a method for reversibly rendering a male mammal infertile, whichcomprises the step of administering to said male mammal an effectiveamount of a compound of formula (I).

(xxx) a method for the treatment of obesity, which comprises the step ofadministering to a patient an effective amount of a compound of formula(I).

(xxxi) a method for the treatment of inflammatory diseases or disordersassociated with macrophage recruitment and activation, including but notlimited to, rheumatoid arthritis, Crohn's disease, asthma and sepsis;which comprises the step of administering to a patient an effectiveamount of a compound of formula (I).

The invention also provides for the use of a compound of formula (I) forthe treatment of the above mentioned diseases and conditions.

All publications, including, but not limited to, patents and patentapplications, cited in this specification, are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The invention will now be described by reference to the followingexamples, which are merely illustrative and are not to be construed as alimitation of the scope of the present invention.

EXAMPLES Example 1 Benzamide,N-[(4-fluorophenyl)methyl]4-[[(2S,3S,4R,5S)-3,4,5-trihydroxy2-(hydroxymethyl)-1-piperidinyl]methyl]-

To a mixture of 3,4,5-piperidinetriol, 2(hydroxymethyl)-, (2S,3S,4R,5S)(50 mg, 0.31 mmol) and (polystyrylmethyl)trimethylammoniumcyanoborohydride (178 mg, 0.76 mmol) in 10% acetic acid in methanol (2ml) was added N-[(4-fluorophenyl)methyl]-4-formylbenzamide (196 mg, 0.76mmol) and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was purified using a plug of acidicDowex 50WX-12 resin (3 g), which had been pre-washed with 10% aqueoushydrochloric acid. The resin was eluted with methanol (25 ml) to removeall non-basic side products. The desired compound was eluted using asolution of 2:2:1 methanol/water/ammonium hydroxide (100 ml). Theresulting solution was concentrated to a small volume (1 ml) and freezedried to afford the title compound as a white solid (70 mg, 57%). ¹H NMR(d4-methanol) δ 2.52 (1H, m), 2.65 (1H, m), 2.78 (1H, m), 3.60-4.16 (7H,m), 4.5-4.7 (2H, m), 7.06 (2H, m), 7.38 (2H, m), 7.52 (2H, d, J=8 Hz),7.82 (2H, d, J=8 Hz). MS m/z 404.9 (M)⁺.

Example 2 3,4,5-Piperidinetriol,2-(hydroxymethyl)-1-[[4-(phenylmethoxy)phenyl]methyl]-, (2S,3S,4R,5S)

To a mixture of 3,4,5-piperidinetriol, 2-hydroxymethyl)-(2S,3S,4R,5S) (5mg, 0.31 mmol) and (polystyrylmethyl)trimethylammonium cyanoborohydride(178 mg, 0.76 mmol) in 10% acetic acid in methanol (2 ml) was added(4-phenylmethoxy)benzaldehyde (162 mg, 0.76 mmol) and the reactionmixture was stirred at room temperature overnight. The reaction mixturewas purified using a plug of acidic Dowex 50WX-12 resin (3 g), which hadbeen pre-washed with 10% aqueous hydrochloric acid. The resin was elutedwith methanol (25 ml) to remove all non-basic side products. The desiredcompound was eluted using a solution of 2:2:1 methanol/water/ammoniumhydroxide (100 ml). The resulting solution was concentrated to a smallvolume (1 ml) and freeze dried to afford the title compound as a whitesolid (30 mg, 27%). ¹H NMR (d4-methanol) δ 2.52 (1H, m), 2.64 (1H, m),2.75 (1H, m), 3.53-4.0 (7H, m), 5.15 (2H, s), 6.95 (2H, d, J=8.3 Hz),7.25-7.48 (7H, m). MS m/z 360.0 (M+H)⁺.

Example 3 Benzamide,N-[1-(S)-(phenyl)ethyl]-4-[[(2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-

To a mixture of 3,4,5-piperidinetriol, 2-(hydroxymethyl)-, (2S,3S,4R,5S)(50 mg, 0.31 mmol) and (polystyrylmethyl)trimethylammoniumcyanoborohydride (178 mg, 0.76 mmol) in 10% acetic acid in methanol (2ml) was added N-[1-S)-phenyl)ethyl]-4-formylbenzamide (193 mg, 0.76mmol) and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was purified using a plug of acidicDowex 50WX-12 resin (3 g), which had been pre-washed with 10% aqueoushydrochloric acid. The resin was eluted with methanol (25 ml) to removeall non-basic side products. The desired compound was eluted using asolution of 2:2:1 methanol/water/ammonium hydroxide (100 ml). Theresulting solution was concentrated to a small volume (1 ml) and freezedried to afford the title compound as a white solid (10 mg, 8%). ¹H NMR(d4-methanol) δ 1.51 (3H, d, J=7.1 Hz), 2.53 (1H, dd, J=6.8 and 12.1Hz), 2.66 (1H, dd, J=3.8 and 12.1 Hz), 2.79 (1H, m), 3.62-4.00 (6H, m),4.13 (1H, d, J=13.6 Hz), 5.25 (1H, m), 7.24 (1H, t, J=7.2 Hz), 7.3-7.4(4H, m), 7.52 (2H, d, J=8.3 Hz), 7.81 (2H, d, J=8.3 Hz). MS m/z 401.0(M+1)⁺.

Example 4 3,4,5-Piperidinetriol,1-[(3-cyano-4-(dipropylamino)phenyl)methyl]-2-(hydroxymethyl),(2S,3S,4R,5S)

To a mixture of 3,4,5-piperidinetriol, 2-hydroxymethyl)-, (2S,3S,4R,5S)(50 mg, 0.31 mmol) and (polystyrylmethyl)trimethylammoniumcyanoborohydride (178 mg, 0.76 mmol) in 10% acetic acid in methanol (2ml) was added 3-cyano-4-(dipropylamino)benzaldehyde (162 mg, 0.76 mmol)and the reaction mixture was stirred at room temperature overnight. Thereaction mixture was purified using a plug of acidic Dowex 50WX-12 resin(3 g), which had been pre-washed with 10% aqueous hydrochloric acid. Theresin was eluted with methanol (25 ml) to remove all non-basic sideproducts. The desired compound was then eluted using a solution of 2:2:1methanol/water/ammonium hydroxide (100 ml). The resulting solution wasconcentrated to a small volume (1 ml) and freeze dried to afford thetitle compound as a white solid (30 mg, 27%). ¹H NMR (d4-methanol) δ0.93 (6H, t, J=7.3 Hz), 1.6 (4H, m), 2.5-2.85 (3H, m), 3.34 (4H, m),3.55-4.05 (7H, m), 7.03 (1H, d, J=9 Hz), 7.5 (1H, dd, J=1.9 and 9 Hz),7.61 (1H, d, J=1.9 Hz). MS m/z 378.1 (M+H)⁺.

Example 5 Benzamide,N-[1-(S)-(4-fluorophenyl)ethyl]-4-[[(2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-

To a mixture of 3,4,5-piperidinetriol, 2-(hydroxymethyl)-, (2S,3S,4R,5S)(50 mg, 0.31 mmol) and (polystyrylmethyl)trimethylammoniumcyanoborohydride (178 mg, 0.76 mmol) in 10% acetic acid in methanol (2ml) was added N-[1S)-(4-fluorophenyl)ethyl]-4-formylbenzamide (207 mg,0.76 mmol) and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was purified using a plug of acidicDowex 50WX-12 resin (3 g), which had been pre-washed with 10% aqueoushydrochloric acid. The resin was eluted with methanol (25 ml) to removeall non-basic side products. The desired compound was then eluted usinga solution of 2:2:1 methanol/water/ammonium hydroxide (100 ml). Theresulting solution was concentrated to a small volume (1 ml) and freezedried to afford the title compound as a white solid, 30 mg (24%). ¹H NMR(d4-methanol) δ 1.57 (3H, d, J=6.8 Hz), 2.54 (1H, dd, J=6.4 and 12.1Hz), 2.65 (1H, dd, J=3.8 and 12.1 Hz), 2.79 (1H, m), 3.6-3.98 (6H, m),4.12 (1H, d, J=14 Hz), 5.23 (1H, q, J=7.2 Hz), 7.06 (2H, m), 7.43 (2H,m), 7.52 (2H, d, J=8.3 Hz), 7.81 (2, d, J=8.3 Hz). MS m/z 419.0 (M+H)⁺.

Example 6 Benzamide,N-[1-(R)-(phenyl)ethyl]4-[[(2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-

To a mixture of 3,4,5-piperidinetriol, 2-(hydroxymethyl)-, (2S,3S,4R,5S)(150 mg, 0.92 mmol) and (polystyrylmethyl)trimethylammoniumcyanoborohydride (540 mg, 2.3 mmol) in methanol (5 ml) was addedN-[1-(R)-phenyl)ethyl]-4-formylbenzamide (910 mg, 3.59 mmol).Dichloromethane (1 ml) was added to dissolve the aldehyde and themixture warmed to dissolve the amine. Acetic acid (0.1 ml, 1.75 mmol)was added to the reaction mixture which was then stirred at roomtemperature overnight. The reaction mixture was purified using a plug ofacidic Dowex 50WX-12 resin (5 g) (which had been pre-washed with 10%aqueous hydrochloric acid, water and then methanol). The resin waseluted with methanol (25 ml) to remove all non-basic side products. Thedesired compound was then eluted using a solution of 4:1methanol/ammonium hydroxide (50 nm), then 3:1:1methanol/dichloromethane/ammonium hydroxide (50 ml). The resultingsolution was concentrated to give a gum which was dissolved in hotwater, cooled and freeze dried to afford the title compound as a whitesolid (300 mg 81%). ¹H NMR (d4-methanol) δ 1.56 (3H, d, J=7.0 Hz), 2.51(1H, dd, J=6.8 and 12.0 Hz), 2.64 (1H, dd, J=3.8 and 12.0 Hz), 2.77 (1H,ddd, J=4.5, 5.3 and 6.0 Hz), 3.64 (1H, dd, J=3.4 and 6.4 Hz), 3.67 (1H,d, J=13.9 Hz), 3.73 (1H, ddd, J=3.8, 6.4 and 6.8 Hz), 3.83 (1H, dd,J=5.3 and 11.7 Hz), 3.91 (1H, dd, J=4.5 and 11.7 Hz), 3.96 (1H, dd,J=3.4 and 6.0 Hz), 4.12 (1H, d, J=13.9 Hz), 5.24 (1H, q, J=7.0 Hz), 7.22(1H, t, J=7.2 Hz), 7.32 (2H, t, J=7.2 Hz), 7.39 (2H, d=7.2 Hz), 7.50(2H, d, J=8.3 Hz), 7.80 (2H, d, J=8.3 Hz). MS m/z 401.2 (M+H)⁺.

Example 7 Benzamide,N-[1-(R)-(4-fluorophenyl)ethyl]-4-[[(2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-

To a mixture of 3,4,5-piperidinetriol, 2-(hydroxymethyl)-, (2S,3S,4R,5S)(50 mg, 0.31 mmol) and (polystyrylmethyl)trimethylammoniumcyanoborohydride (178 mg, 0.76 mmol) in 10% acetic acid in methanol (2ml) was added N-[1-(R)(4-fluorophenyl)ethyl]-4-formylbenzamide (207 mg,0.76 mmol) and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was purified using a plug of acidicDowex 50WX-12 resin (3 g) (which had been pre-washed with 10% aqueoushydrochloric acid). The resin was eluted with methanol (25 ml) to removeall non-basic side products. The desired compound was then eluted usinga solution of 2:2:1 methanol/water/ammonium hydroxide (100 ml). Theresulting solution was concentrated to a small volume (1 ml) and freezedried to afford the title compound as a white solid, 40 mg (31%). ¹H NMR(d4-methanol) δ 1.55 (3H, d, J=7.1 Hz), 2.52 (1H, dd, J=6.8 and 12.0Hz), 2.64 (1H, dd, J=3.8 and 12.0 Hz), 2.77 (1H, ddd, J=4.5, 5.1 and 5.9Hz), 3.64 (1H, dd, J=3.4 and 6.4 Hz), 3.67 (1H, d, J=14 Hz), 3.74 (1H,ddd, J=3.8, 6.4 and 6.8 Hz), 3.83 (1H, dd, J=5.1 and 11.5 Hz), 3.91 (1H,dd, J=4.5 and 11.5 Hz), 3.96 (1H, dd, J=3.4 and 6.0 Hz), 4.12 (1H, d,J=14 Hz), 5.22 (1H, q, J=7.1 Hz), 7.05 (2H, dd, J=8.7 and 8.9 Hz), 7.41(2H, dd, J=5.6 and 8.7 Hz), 7.50 (2H, d, J=8.1 Hz), 7.79 (2H, d, J=8.1Hz). MS m/z 419.1 (M+H)⁺.

Example 8 3,4,5-Piperidinetriol,2-(hydroxymethyl)-1-[(2-phenyl-2H-1,4-benzoxazin-3(4H)-one-6-yl)methyl]-,(2S,3S,4R,5S)

To a mixture of 3,4,5-piperidinetriol, 2-(hydroxymethyl)-, (2S,3S,4R,5S)(50 mg, 0.31 mmol), 2-phenyl-2H-1,4-benzoxazin-3(4H)-one-6-carbaldehyde(230 mg, 0.91 mmol) and (polystyrylmethyl)trimethylammoniumcyanoborohydride (300 mg, 1.31 mmol) in methanol (2 ml) was added aceticacid (0.2 ml). The resultant mixture was stirred at room temperature for16 h. The crude reaction mixture was purified using a plug of acidicDowex 50×4-200 resin (1 g) (which had been pre-washed with methanol (10ml)). The resin was eluted with methanol (25 ml) to remove all non-basicside products. The desired compound was then eluted using a solution of7:1 methanol/ammonium hydroxide (25 ml). The resulting solution wasconcentrated to a small volume (1 ml) and freeze dried. The freeze driedsolid was further purified using silica chromatography (gradient elution10 to 30% methanol/dichloromethane and 1% ammonia) to afford the titlecompound as a white solid (34 mg, 27%). —HNMR (d4-methanol) δ 2.62 (1H,m), 2.75 (1H, m), 2.87 (1H, m), 3.66-4.11 (7H, m), 5.69 (1H, s),6.94-7.05 (3H, m), 7.32-7.45 (5H, m). MS m/z 401.2 (M+H)⁺.

Example 9 3,4,5-Piperidinetriol,2-(hydroxymethyl)-1-[[4-[(4-chlorophenyl)methoxy]phenyl]methyl]-,(2S,3S,4R,5S)

To a mixture of 3,4,5-piperidinetriol, 2-hydroxymethyl)-(2S,3S,4R,5S)(57 mg, 0.35 mmol) and (polystyrylmethyl)trimethylammoniumcyanoborohydride (253 mg, 1.08 mmol) in 10% acetic acid in methanol (2ml) was added 4-[(4-chlorophenyl)methoxy] benzaldehyde (280 mg, 1.13mmol) and the reaction mixture was stirred at room temperature for twodays. The reaction mixture was purified using a plug of acidic Dowex50WX-12 resin (1 g), which had been pre-washed with methanol. The resinwas r eluted with methanol (25 ml) and acetone (100 ml) to remove allnon-basic side products. The desired compound was eluted using asolution of 7:1 methanol/ammonium hydroxide (50 ml). The resultingsolution was concentrated, re-dissolved in methanol and pre-adsorbedonto silica gel. The product was then eluted through a silica gel columnusing methanol as solvent, concentrated to a gum, and freeze dried toafford the title compound as a white solid (64 mg, 46%). ¹H NMR(d4-methanol) δ 2.51 (1H, m), 2.63 (1H, m), 2.74 (1H, m), 3.53-4.0 (7H,m), 5.05 (2H, s), 6.93 (2H, d, J=8.7 Hz), 7.29 (2H, d, J=8.7 Hz), 7.37(2H, d, J=8.5 Hz), 7.43 (2H, d, J=8.5 Hz). MS m/z 394.1, 396.1 (M+H)⁺.

Example 10 3,4,5-Piperidinetriol,2-(hydroxymethyl)-1-[[4[(4-fluorophenyl)methoxy]phenyl]methyl]-,(2S,3S,4R,5S)

To a mixture of 3,4,5-piperidinetriol, 2-(hydroxymethyl)-(2S,3S,4R,5S)(57 mg, 0.35 mmol) and (polystyrylmethyl)trimethylammoniumcyanoborohydride (250 mg, 1.07 mmol) in 10% acetic acid in methanol (2ml) was added 4-[(4-fluorophenyl)methoxy]benzaldehyde (250 mg, 1.08mmol) and the reaction mixture was stirred at room temperature for twodays. The reaction mixture was purified using a plug of acidic Dowex50WX-12 resin (1 g), which had been pre-washed with methanol. The resinwas eluted with methanol (25 ml) and ethyl acetate (100 ml) to removeall non-basic side products. The desired compound was eluted using asolution of 7:1 methanol/ammonium hydroxide (100 ml). The resultingsolution was concentrated, re-dissolved in methanol and pre-adsorbedonto silica gel. The product was then eluted through a silica gel columnusing methanol as solvent, concentrated to a gum, and freeze dried toafford the title compound as a white solid (56 mg, 42%). ¹H NMR(d4-methanol) δ 2.57 (1H, m), 2.69 (1H, m), 2.80 (1H, m), 3.60-4.10 (7H,m), 5.05 (2H, s), 6.95 (2H, d, J=8.5 Hz), 7.09 (2H, m), 7.31 (2H, d,J=8.5 Hz), 7.45 (2H, m). MS m/z 378.1 (M+H)⁺.

Biological Assays

The compounds of the invention may be tested for their biologicalactivity in the following assays:

Inhibition of GCS

The assay for inhibition of GCS was performed essentially as describedin Platt et al., J. Biol. Chem., (1994), 269, 27108, the enzyme sourcebeing human recombinant GCS expressed in insect cells.

Inhibition of non-lysosomal-β-glucocerebrosidase

The assay for inhibition of non-lysosomal-β-glucocerebrosidase wasessentially carried out as described in Overkleeft, H. S. et al., J.Biol. Chem., (1998) 273, 26522-26527 with the following differences:whole cell extracts of MCF7 (a human breast carcinoma cell line) wasused as the source of the enzyme instead of splenic membranesuspensions; 5mM instead of 3Mm, 4-MU β-glucoside was used as substrateand 0.2M citrate/phosphate (pH 5.8) was used instead of McIlvainebuffer.

Table I shows IC₅₀ data for compounds of the invention against human GCSand non-lysosomal-β-glucocerebrosidase enzymes. TABLE I Inhibition ofnon-lysosomal-β- Inhibition of GCS glucocerebrosidase Compound (IC₅₀ μM)(IC₅₀ μM) Example 1 2.20 100.00 Example 2 0.66 9.40 Example 3 7.20 14.90Example 4 0.62 1.93 Example 7 4.70 >100.00

Estimating the Cell-Based Ic₅₀ for GCS Inhibition by MeasuringGlucosylceramide (GlcCer) Depletion

Human mammary epithelial cells (MCF-7) were cultured for 5-7 days, withvarying concentrations of a compound of the invention to be tested (0;0.01; 0.05; 0.25; 1.25 and 6.25 μM). The cells were harvested and thetotal cellular lipids extracted. Neutral glycolipids were separated bypartitioning in a DIPE/1-butanol/saline suspension, according to methodswell known to those skilled in the art. The neutral glycolipid extractswere then separated by High-Performance Thin Layer Chromatography(HPTLC), using non-polar TLC conditions (chloroform:methanol: 0.2%CaCl₂; 65:35:8), according to methods well known to those skilled in theart GlcCer bands were visualized and the TLC plates were scannedimmediately. Scion Image software was then used to quantify GIcCer inthe samples relative to a GIcCer standard. This enabled a cell-basedIC₅₀ to be calculated for compounds of the invention for GCS inhibition,as shown in the Table II.

Table II shows cell-based IC₅₀ data for compounds of the inventionagainst human GCS. TABLE II Inhibition of GCS Compound Cellular-based(IC₅₀ μM) Example 2 <0.10 Example 6 1.00

1. A compound of formula (I) or a pharmaceutically acceptable salt orprodrug thereof:

wherein R is C₁₋₃ alkylAr¹ where Ar¹ is phenyl or pyridyl; whereinphenyl is substituted by one or more substituents selected from CN,CON(R¹)₂, SO_(n)R², SO₂N(R¹)₂, N(R⁵)₂, N(R¹)COR², N(R¹)SO_(n)R², C₀₋₆alkylAr², C₂₋₆ alkenylAr² and C₃₋₆ alkynylAr² wherein one or more of the—CH₂— groups of the alkyl chain may be replaced with a heteroatomselected from O, S and NR³, provided that when the heteroatom is O, atleast two —CH₂— groups separate it from any additional O atom in thealkyl chain; or two adjacent substituents on the Ar¹ phenyl may togetherform a fused 5- or 6-membered saturated or unsaturated ring wherein thering optionally contains 1 or 2 heteroatoms selected from O, S and NR⁴and is optionally substituted by one or more substituents selected from,an oxo group, C₁₋₆ alkyl and C₀₋₃ alkylAr⁴; and the Ar¹ phenyl isoptionally substituted by one or more additional substituents selectedfrom F, Cl, Br, CF₃, OCF₃, OR³ and C₁₋₆ alkyl; and wherein pyridyl issubstituted by one or more substituents, selected from, CN, CON(R¹)₂,SO_(n)R², SO₂N(R¹)₂, N(R⁵)₂, N(R¹)COR², N(R¹)SO_(n)R², F, Cl, Br, CF₃,OCF₃, OR³, C₁₋₆ alkyl, C₀₋₆ alkylAr², C₂₋₆ alkenylAr² and C₃₋₆alkynylAr² wherein one of the —CH₂— groups of the alkyl chain may bereplaced with a heteroatom selected from O, S and NR³, provided thatwhen the heteroatom is O, at least two —CH₂— groups separate it from anyadditional O atom in the alkyl chain; or two adjacent substituents onthe Ar′ pyridyl may together form a fused 5- or 6-membered saturated orunsaturated ring wherein the ring optionally contains 1 or 2 heteroatomsselected from O, S and NR⁴ and is optionally substituted by one or moresubstituents selected from, an oxo group, C₁₋₆ alkyl and C₀₋₃ alkylAr⁴;R¹ is H, C₁₋₆ alkyl optionally substituted by OH, Ar³, or C₁₋₆ alkylAr³,or the group N(R¹)₂ may form a 5- to 10-membered heterocyclic groupoptionally containing one or more additional heteroatoms selected fromO, S and NR³ and is optionally substituted by an oxo group; R² is C₁₋₆alkyl optionally substituted by OH, Ar³, or C₁₋₆ alkylAr³; R³ is H, orC₁₋₆ alkyl; R⁴ is H, C₁₋₆ alkyl or C₀₋₃alkylAr⁴; R⁵ is H, C₁₋₆ alkyloptionally substituted by OH, Ar³, or C₁₋₆ alkylAr³, or the group N(R⁵)₂may form a 5- to 10-membered heterocylic group optionally containing oneor more additional heteroatoms selected from O, S and NR³ and isoptionally substituted by an oxo group; Ar² and Ar³ are independentlyphenyl or a 5- to 10-membered heteroaryl group containing up to 3heteroatoms selected from O, S and NR³, which may be optionallysubstituted by one or more substituents selected from F, Cl, Br, CN,CF₃, OCF₃, OR³ and C₁₋₆ alkyl; Ar⁴ is phenyl or pyridyl either of whichmay be optionally substituted by one or more substituents selected fromF, Cl, Br, CN, CF₃, OCF₃, OR³ and C₁₋₆ alkyl; and n=0, 1 or
 2. 2. Acompound as defined in claim 1 wherein R is C₁alkylAr¹.
 3. A compound asdefined in claim 1, wherein Ar¹ is phenyl, wherein phenyl is substitutedas defined in claim
 1. 4. A compound as defined in claim 1, wherein Ar¹is phenyl, wherein phenyl is substituted by one or more substituentsselected from CN, CON(R¹)₂, N(R⁵)₂, and C₀₋₆ alkylAr² wherein one ormore of the —CH₂— groups of the alkyl chain may be replaced with aheteroatom selected from O, S and NR³, provided that when the heteroatomis O, at least two —CH₂— groups separate it from any additional O atomin the alkyl chain, or two adjacent substituents on the Ar¹ phenyl maytogether form a fused 5- or 6-membered saturated or unsaturated ringwherein the ring optionally contains 1 or 2 heteroatoms selected from Oand NR⁴ and is optionally substituted by one or more substituentsselected from, an oxo group, C₁₋₆ alkyl and C₀₋₃ alkylAr⁴, and the Ar¹phenyl is optionally substituted by one or more additional substituentsselected from F, Cl, Br, CF₃, OCF₃, OR³ and C₁₋₆ alkyl.
 5. A compound asdefined in claim 1, wherein Ar¹ is phenyl, wherein phenyl is substitutedby one or more substituents selected from CN, CON(R¹)₂, N(R⁵)₂, and C₀₋₆alkylAr² wherein one or more of the —CH₂— groups of the alkyl chain maybe replaced with 0, provided that at least two —CH₂— groups separate itfrom any additional O atom introduced into the alkyl chain and the Ar¹phenyl is optionally substituted by one or more additional substituentsselected from F, Cl, Br, CF₃, OCF₃, OR³ and C₁₋₆ alkyl.
 6. A compound asdefined in claim 1, wherein Ar² is phenyl which is optionallysubstituted by one or more substituents selected from F, Cl, Br, CN,CF₃, OCF₃, OR³ and C₁₋₆ alkyl.
 7. A compound as defined in claim 1,wherein R¹ is H or C₁₋₆ alkylAr³.
 8. A compound as defined in claim 1,wherein R⁴ is H or C₁₋₆ alkyl.
 9. A compound as defined in claim 1wherein Ar³ is phenyl which may be optionally substituted by one or moresubstituents selected from F, Cl, Br, CN, CF₃, OCF₃, OR³ and C₁₋₆ alkyl.10. A compound as defined in claim 1 wherein R⁵ is C₁₋₆ alkyl.
 11. Acompound selected from Benzamide,N-[(4-fluorophenyl)methyl]-4-[[2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-;3,4,5-Piperidinetriol,2-(hydroxymethyl)-1-[[4-(phenylmethoxy)phenyl]methyl]-,(2S,3S,4R,5S);Benzamide,N-[1-(S)-(phenyl)ethyl]-4-[[(2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-;3,4,5-Piperidinetriol,1-[(3-cyano-4-(dipropylamino)phenyl)methyl]-2-(hydroxymethyl)-,(2S,3S,4R,5S); Benzamide,N-[1-(S)-(4-fluorophenyl)ethyl]-4-[[2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-;Benzamide,N-[1-(R)-(phenyl)ethyl]-4-[[2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-;Benzamide,N-[1-(R)-(4-fluorophenyl)ethyl]-4-[[2S,3S,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl]methyl]-;3,4,5-Piperidinetriol,2-(hydroxymethyl)-1-[(2-phenyl-2H-1,4-benzoxazin-3(4H)-one-6-yl)methyl]-,(2S,3S,4R,5S); 3,4,5-Piperidinetriol,2-(hydroxymethyl)-1-[[4-[(4-chlorophenyl)methoxy]phenyl]methyl]-,(2S,3S,4R,5S); 3,4,5-Piperidinetriol,2-(hydroxymethyl)-1-[[4-[(4-fluorophenyl)methoxy]phenyl]methyl]-,(2S,3S,4R,5S); and pharmaceutically acceptable salts or prodrugsthereof.
 12. (canceled)
 13. A pharmaceutical composition comprising acompound of formula (I) as defined in claim 1, together with one or morepharmaceutically acceptable carriers, excipients and/or diluents.
 14. Aprocess for the preparation of a compound of formula (I) as defined inclaim 1, the process comprising: a) reductive amination of an aldehydeof formula R⁵CHO wherein R⁵ is C₀₋₂ alkylAr¹ where Ar¹ is as defined inclaim 1, with a compound of formula (II):

or b) deprotection of a compound of formula (III):

wherein R is as defined in claim 1 and P, which may be the same ordifferent, are hydroxy protecting groups.
 15. A method of inhibitingglucosylceramide synthase in a patient in need thereof, comprisingadministering to the patient an effective amount of a compound offormula (I) as defined in claim
 1. 16. A method of treating a glycolipidstorage disease in a patient in need thereof, comprising administeringto the patient an effective amount of a compound of formula (I) asdefined in claim
 1. 17. The method of claim 16, wherein the glycolipidstorage disease is Gaucher disease, Sandhoffs disease, Tay-Sachsdisease, Fabry disease or GM1 gangliosidosis.
 18. A method of treating adisorder selected from Niemann-Pick disease type C,mucopolysaccharidosis type I, mucopolysaccharidosis type IIIA,mucopolysaccharidosis type IIIB, mucopolysaccharidosis type VI,mucopolysaccharidosis type VII, α-mannosidosis and mucolipidosis type IVin a patient in need thereof, comprising administering to the patient aneffective amount of a compound of formula (I) as defined in claim
 1. 19.A method of treating cancer in which glycolipid synthesis is abnormal ina patient in need thereof, comprising administering to the patient aneffective amount of a compound of formula (I) as defined in claim
 1. 20.The method of claim 19, wherein the cancer in which glycolipid synthesisis abnormal is selected from brain cancer, neuronal cancer,neuroblastoma, renal adenocarcinoma, malignant melanoma, multiplemyeloma and multi-drug resistant cancer.
 21. A method of treating adisorder selected from Alzheimer's disease, epilepsy, stroke,Parkinson's disease and spinal injury in a patient in need thereof,comprising administering to the patient an effective amount of acompound of formula (I) as defined in claim
 1. 22. A method of treatingdiseases caused by (i) infectious microorganisms which utilizeglycolipids on the surface of cells as receptors for either the organismitself or for toxins produced by the organism, or (ii) infectiousorganisms for which the synthesis of glucosylceramide is an essential orimportant process, in a patient in need thereof, comprisingadministering to the patient an effective amount of a compound offormula (I) as defined in claim
 1. 23. A method of treating diseasesassociated with abnormal glycolipid synthesis in a patient in needthereof, comprising administering to the patient an effective amount ofa compound of formula (I) as defined in claim
 1. 24. A method oftreating a condition treatable by the administration of a ganglioside ina patient in need thereof, comprising administering to the patient aneffective amount of a compound of formula (I) as defined in claim
 1. 25.The method of claim 24, wherein the condition is treatable by theadministration of a GM1 ganglioside.
 26. A method of reversiblyrendering a male mammal infertile, comprising administering to the malemammal an effective amount of a compound of formula (I) as defined inclaim
 1. 27. A method of treating obesity in a patient in need thereof,comprising administering to the patient an effective amount of acompound of formula (D) as defined in claim
 1. 28. A method of treatinginflammatory diseases or disorders associated with macrophagerecruitment and activation in a patient in need thereof, comprisingadministering to the patient an effective amount of a compound offormula (I) as defined in claim
 1. 29. The method of claim 28, whereinthe inflammatory disease or disorder associated with macrophagerecruitment and activation is selected from rheumatoid arthritis,Crohn's disease, asthma and sepsis.
 30. A compound of formula (III):

wherein R is as defined in claim 1 and P, which may be the same ordifferent, are hydroxy protecting groups.